Any penetration of the skin carries with it the risk of potential infection. This risk pertains to simple wounds incurred by accident or negligence; to surgical procedures performed under controlled conditions which utilize different biomaterials for the closure and dressing of incisions and/or wounds; and to a diverse range of in-vivo implantable textile fabrics, configured textile articles, and textile-containing mechanical appliances and devices which are surgically introduced into the body for diagnostic, therapeutic and/or prosthetic purposes.
The rational use of antimicrobial agents against infection, particularly for simple wound treatment, has been advocated generally and has been previously reviewed in detail [Rodgers, K. G., Emer. Med. Clin. N. Am. 10: 753 (1992)]. Similarly, the major concerns regarding the ever-growing incidence of infections resulting from biocompatible textiles, articles and devices implanted in the bodyxe2x80x94espite recent advances in sterile procedures used in the clinical/surgical settingxe2x80x94have been considered and reviewed as the primary purpose and focus of a FDA/EPA/CDC/AAMI joint conference [Proceedings, Infection Control Symposium: Influence Of Medical Device Design, U.S. Dept. of Health and Human Services, Bethesda, Md., January 1995]. Moreover, the use of antibiotics and of mechanisms for delivering antimicrobial agents generally, particularly via slow-release delivery systems over time, to prevent or reduce severity of infection for implanted biodegradable materials has been reviewed [Sasmor et al., J. Vasc. Sur. 14: 521 (1993)]. All of these considerations lead to the same conclusion: Infection, with or without the use of antibiotics, must be prevented or be controlled for all implantable biomaterials (including textiles, articles and devices) regardless of need or medical purpose.
Infection of Implantable Biomaterials
Infection of implantable biomaterials, specifically prosthetic vascular grafts, is an ever-growing problem and concern. For example, prosthetic vascular grafts, which are composed primarily of either polyester or polytetrafluoroethylene (PTFE), are a source of significant clinical morbidity and mortality upon infection [Goldstone, J. and W. S. Moore, Am. J. Surg. 128: 225 (1974); Liekweg et al., Surgery 81: 335 (1977); Bunt, T. J., Surgery 93: 733 (1983); Golan, J. F., Infect. Dis. Clin. N. Am., 3: 247 (1989); Sugarman, B. and E. J. Young, Infect. Dis. Clin. N. Am. 3: 187 (1989)], significantly impacting patient quality of life. Graft infection occurs in 2-6% of all clean cases performed [Hoffert et al., Arch. Surg. 90: 427 (1965); Fry, W. L. and S. M. Lindenauer, Arch. Surg. 94: 600 (1966); Rittenhouse et al. Ann. Surg. 170: 87 (1969); Drapanas et al., Ann. Surg. 172: 351 (1970); Szilagyi et al., Ann. Surg. 176: 321 (1972)], with morbidity and mortality related to the anatomic position of the graft. Infectious inoculation of the biomaterial presumably occurs at the time of implantation or as a result of transient bacteremia in the immediate post-operative period [Cheri et al., J. Vasc. Surg. 14: 521 (1991)]. Peri-operative parental antibiotics, while having a defined role in wound infection prophylaxis, often fail to permeate the avascular spaces immediately around prosthetic grafts as well as the carbohydrate-rich bacterial biofilm once pathogens have adhered [Gristina, A. G., Science 237: 1585 (1987); Kaiser et al., Ann. Surg. 188: 283 (1978); Greco, R. S., J. Vasc. Surg. 13: 5 (1991); Bandyk et al., J. Vasc. Surg. 13: 575 (1991)].
The two main types of bacteria responsible for graft infection are the coagulase negative Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). S. aureus has been shown to be responsible for 65-100% of acute (days to weeks) infections (3,14). Typically, these infections develop rapidly and generate an intense response by the host defense mechanisms. An ever-increasing problem (which has been documented both in animal models and in humans) is the susceptibility of vascular prostheses to later (months to years) infection. S. epidermidis has emerged as the leading isolate from infection vascular conduits (20-60%) with infection appearing late after implantation. Both of these instances are clearly not affected by low level antibiotic transiently occurring at the time of surgery. A decreased amount of antibiotic may also play a role in the development of resistant organisms.
Health care costs for graft infection should also be considered since the onset of this complication results in elevated patient care costs. In 1989, approximately $150M was spent on the implantation of synthetic arterial grafts in the United States. Using the estimated infection rates, approximately $3 to $9 million has been spent to implant another vascular graft external of the infection site, a procedure required to prevent subsequent infection and failure of the replacement graft. The cost of treating infection, the mortality that occurs in some 25% of infected cases and inflation also must be included. Thus, the overall total impact of graft infection on health care costs can only be estimated, however, the magnitude of the problem is extremely significant, driving the research to develop infection-resistant biomaterials.
Conventional Efforts To Combat Graft Surface Infections
Numerous strategies have been attempted in order to create an infection-resistant graft surface for biomaterials. Chelating agents have been evaluated as a release system for antibiotics from a biomaterial surface. One approach which has been the subject of numerous investigations was the ionic binding of antibiotics by surfactants. Cationic surfactants such as tridodecylmethyl ammonium chloride and benzalkonium chloride were sorbed at the anionic surface potential of a polymeric material, thereby permitting weak adhesion of anionic antibiotics to the surface [Harvey et al., Ann. Surg. 194: 642 (1981); Harvey et al., Surgery 92: 504 (1982); Harvey et al., Am. J. Surg. 147: 205 (1984); Shue et al., J. Vasc. Surg. 8: 600 (1988); Webb et al., J. Vasc. Sur. 4: 16 (1956)]. The selected antibiotic was then released upon contact with blood. Silver was also examined as a release system for various antibiotics from graft surfaces, applied either as a chelating agent [Modak et al., Surg. Gynecol. Obstet. 164: 143 (1987); Benvenisty et al., J. Surg. Res. 44: 1 (1988); White et al., J. Vasc. Surg. 1: 372 (1984)] or alone due to its antimicrobial properties.
Binding agents have also been employed in order to create localized concentrations of antibiotic on the graft surface. These agents, which were either protein or synthetic-based, were embedded within the biomaterial matrix thereby either xe2x80x9ctrappingxe2x80x9d or ionically binding the antibiotic. The basement membrane protein collagen has served as a release system for rifampin, demonstrating antimicrobial efficacy in a bacteremic challenge dog model [Krajicek et al., J. Cardiovasc. Surg. 10: 453 (1969)] as well as in early European clinical trials [Goeau-Brissonniere, O., J. Mal. Vasc. 21: 146 (1996); Strachan et al., Eur. J. Vasc. Surg. 5: 627 (1991)]. Fibrin, either as a pre-formed glue or in pre-clotted blood, has been utilized as a binding agent for various antibiotics including gentamycin, rifampin and tobramycin [Haverich et al., J. Vasc. Surg. 14: 187 (1992); McDougal et al., J. Vasc. Surg. 4: 5 (1986); Powell et al., Surgery 94: 765 (1983); Greco et al., J. Biomed. Mater. Res. 25: 39 (1991)].
Levofloxacin has been incorporated in an albumin matrix and gelatin has been used as the release system for the antibiotics rifampin and vancomycin, with animal studies also showing efficacy in acute bacteremic challenges [Muhl et al., Ann. Vasc. Surg. 10: 244 (1996); Sandelic et al., Cardiovasc. Surg. 4: 389 (1990)].
Synthetic binders have also been evaluated for antibiotic release as a replacement for the protein binders. Some synthetic binders were incorporated directly into the biomaterial matrix, in a similar fashion as the protein binders, permitting sustained release of a selected antibiotic over time [Shenk et al., J. Surg. Res. 47: 487 (1989)]. Recent techniques also have utilized these types of binder materials as a scaffolding to covalently bind antibiotics to the biomaterial surface [Suzuki et al., ASAIO J. 43: M854 (1997)]. Release of the antimicrobial agent was controlled by bacterial adhesion to the surface which resulted in antibiotic cleavage. This method promotes xe2x80x9cbacterial suicidexe2x80x9d while maintaining antibiotic, which is not needed to prevent infection, localized on the surface. Other techniques have involved incorporating the antibiotic either into the synthesis process of the polymer [Golomb et al., J. Biomed. Mater. Res. 25: 937 (1991); Whalen et al., ASAIO J. 43: M842 (1997)], or by embedding the antibiotic directly into the interstices of the material [Okahara et al., Eur. J. Vasc. Endovasc. Surg. 9: 408 (1995)].
There are several drawbacks for each of these technologies. For the chelation agents, 50% of the antibiotic has been shown to elute from the graft surface within 48 hours, with less than 5% remaining after three weeks [Greco et al., Arch. Surg2. 120: 71 (1985)]. While this antibiotic coverage is adequate for small localized contaminations, large infectious inoculums are not addressed. For the binding agents, antibiotic release may be quite varied depending on the rate of binder degradation or binder release from a surface which is under high shear stress from blood flow. Comparably, both types of surface modifications rely on exogenous matter which may affect the overall healing of the graft surface, either by releasing toxic moieties or by promoting thrombogenesis. Thus, these potential complications have accentuated the need to create an infection-resistant graft surface which is devoid of exogenous matter such as binding agents.
Use Of Antibiotics As Dyes
Noticeably, all of the above identified reported investigations avoid the examination of any direct material/antibiotic interaction. Some attempts to use direct interactions, particularly dye-fiber interactions as a model, in order to provide infection resistance without exogenous binders have been recently made. Antibiotic release is essential, unlike proteins which are still active when covalently bound. Moreover, dyes have substantivity; and will xe2x80x9cexhaustxe2x80x9d from a bath preferentially into a fiber, when attracted by physical forces of attraction.
Initial efforts in this regard examined the use of commercially available dyes as anchors for antibiotic molecules, and even determined the antibiotic activity of some dyes [see for example: U.S. Pat. No. 5,281,662; and Bide et al., Textile Chemist and Colorist 25: 15-19 (1993). This approach was unrewarding. In contrast, the direct use of antibiotics was examined [Phaneuf et al., J. Biomed. Mat. Res. 27: 233-237 (1993); Ozaki et al., J. Surg. Res. 55: 543-547 (1993); Phaneuf et al., in Antimicrobial/Anti-Infective Materials (Sawan, S. P. and G. Manivannan, editors), Chap. 10, pp. 239-259 (2000); and the references cited within each of these printed publications]. Fluoroquinolone antibiotics are particularly suitable in such applications. They are stable to dry heat and to hot aqueous media; they have an appropriate molecular size, and (in the absence of any reliable method for predicting physical interactions) a somewhat dye-like structure. Two of the most common commercial quinolones which are currently available are Ciprofloxacin (Cipro) and Ofloxacin (Oflox).
Despite all these developments there remains a recognized and continuing need for further improvements in the making of infection-resistant, biomedical materials, devices and configured constructs formed of textile fibers. All such improvements in the making and/or preparation of implantable, textile fiber containing articles of manufacture which could resist microbial infections and inhibit microbial growth would be seen as a crucial advantage and outstanding benefit in this medical field.
The present invention is a major advance in the development of biomedical materials, devices and constructs which are infection resistant. Accordingly, the invention may be used in a wide range of different in-vivo medical, biomedical, and prosthetic applications; and may be summarized as:
A method for making an infection-resistant fabricated textile article useful for biomedical applications in-vivo, said method comprising the steps of:
obtaining a fabricated textile article comprised of at least one type of fiber or fabric matrices able to take up aqueous fluids;
preparing an aqueous antibiotic fluid of predetermined concentration comprising water and at least one water-miscible antibiotic composition which has characteristic antimicrobial properties, is heat stable and has a relative molecular mass in the 300-1500 range;
perfusing said prepared antibiotic fluid across said fibers or fabric matrices of said fabricated textile article for a prechosen period of time such that said prepared antibiotic fluid permeates into at least some of the fibers or fabric matrices comprising said fabricated textile article;
allowing said antibiotic perfused fabricated textile article to dry; and
heating said dried, antibiotic perfused fabricated textile article to an elevated temperature for a predetermined period of time sufficient to incorporate said antibiotic without significant modification to said fibers of said fabricated textile article such that said fiber attached antibiotic retains its characteristic antimicrobial activity.